Introduction

Anemia is generally defined as hemoglobin of less than 13.0 g/dL in men and less than 12.0 g/dL in premenopausal women.[1] Anemia of chronic kidney disease (CKD) is a form of normocytic normochromic, hypoproliferative anemia. Among other complications of CKD, it is frequently associated with poor outcomes in CKD and increases mortality.[2][3]

The disorder starts to develop when the glomerular filtration rate drops to below 60 mg/ml. The anemia is rare when the GFR is above 80 mg/ml. As the GFR worsens, the anemia gets more severe.

Etiology

Anemia in chronic renal disease is a multifactorial condition, the widely accepted etiology being decreased renal production of erythropoietin, the hormone that is responsible for the stimulation of red blood cells production. Decreased erythropoietin has recently linked with downregulation of hypoxia-inducible factor (HIF), a transcription factor that regulates gene expression of erythropoietin.[4][5] Other mechanisms include uremia (leading to RBC deformity responsible for hemolysis), folate and vitamin B12 deficiency, iron deficiency, bleeding due to dysfunctional platelets, and rarely blood loss from hemodialysis.[6] RBC fragmentation by injured renovascular endothelium in selected conditions such as glomerulopathy and malignant hypertension exacerbates the anemia, which explains why anemia can be particularly severe in renal glomerulopathies, including glomerulonephritis, diabetic nephropathy, for the degree of excretory failure.

Epidemiology

The condition usually starts to develop following a greater than 50 percent loss of the kidney function, typically when the glomerular filtration rate (GFR) decreases to less than 60 mL/min.[7] The severity of anemia tends to worsen as chronic kidney disease (CKD) progresses. The deficiency in renal production of erythropoietin and the severity of anemia do not always tend to correlate with the severity of renal dysfunction. At least 90% of patients who end up on dialysis will eventually develop anemia of chronic disease.

History and Physical

Clinical presentation of anemia of renal disease is not different from that of anemia due to other causes. Common symptoms include:

Dyspnea (shortness of breath)

Fatigue

Generalized weakness

Headaches

Decreased concentration

Dizziness

Reduced exercise tolerance.

Commonly observable signs include:

Skin and conjunctival pallor

Respiratory distress

Tachycardia

Chest pain (mostly with severe anemia)

Heart failure (usually with chronic severe anemia)

Evaluation

Common workup required to diagnose the condition include,

CBC with differential

Peripheral smear

Iron indices (iron, ferritin, TIBC, transferrin saturation)

Iron, vitamin B, and folate levels (included in initial workup to rule out other reversible causes of anemia)

Normocytic normochromic anemia and peripheral reticulocytopenia are observable on CBC with a peripheral smear.

Unfortunately, due to high serum ferritin levels secondary to chronic inflammation in CKD, serum iron indices are not accurately indicative of the degree of iron deficiency in dialysis patients, thus raising the standard cutoffs of iron responsiveness.[8][9] The Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE) study demonstrated that intravenous iron is beneficial in dialysis patients even in the setting of ferritin as high as 1200 ng/mL if the transferrin saturation is less than 30%.[10]

Measuring serum erythropoietin levels are discouraged in CKD, and is not usable as an indicator of a renal source of the anemia, because, in kidney disease, there is 'relative erythropoietin deficiency,' that is, an inappropriate rise in erythropoietin levels for the severity of anemia.[11][12]

Bone marrow may show erythroid hypoplasia, which correlates to the reports of resistance of bone marrow to erythropoietin.

Treatment of anemia in CKD has come a long way. Before the advanced treatment options that are available today, the main treatment option used to be blood transfusions, which came with numerous complications including infections, hemosiderosis, fluid overload, transfusion reactions, etc. It started with the use of androgens in the 1970s to avoid transfusion in patients with CKD.[13][14] After that, in the 1980s, the development of recombinant EPO followed by erythropoiesis-stimulating agents (ESAs) revolutionized the management of anemia in CKD.[15] Although initially instituted to avoid transfusions, they were soon known to have various positive effects, including improved survival and quality of life, improved cardiac function and mortality associated with it,[16] lower hospitalizations,[17] and lower costs.[18]

Recombinant human erythropoietin and darbepoetin alfa are the two ESAs generally used in the management of anemia in CKD. They are fairly similar in efficacy and side effect profile, except for the longer half-life of darbepoetin alfa, thus allowing for less frequent dosing.[19][20]

As per KIDGO guidelines, in patients with CKD who are not on dialysis, ESAs are typically considered when hemoglobin level drops below 10 g/dl, but is individualized depending on various factors, including symptoms related to anemia, dependence on transfusions, the rate of drop in hemoglobin concentration, and response to iron therapy. In these patients, erythropoietin (50 to 100 units/kg IV or SC) is usually given every 1 to 2 weeks, and darbepoetin alfa dosing is every 2 to 4 weeks.

In patients who are on dialysis, ESAs are usually avoided unless the hemoglobin level is between 9 and 10 g/dL. In this subset, erythropoietin is given with every dialysis, i.e., three times a week, whereas darbepoetin alfa is dosed to once a week.

Generally, the peak rise in RBCs in response to ESAs occurs at 8 to 12 weeks. However, in around 10% to 20% of cases, anemia can be resistant to ESAs. Common adverse effects of ESAs include seizures, the progression of hypertension, clotting of dialysis access, the progression of malignancy and higher mortality in cancer patients.[21][15]

In all patients with CKD, regardless of the need for dialysis, goal hemoglobin with the use of ESAs is less than 11.5 g/dL. Multiple trials were done to assess the superiority of target hemoglobin to 'high normal' versus lower range. These trials, including CHOIR, NHCT and TREAT trials demonstrated higher mortality, thrombosis, adverse cerebrovascular and cardiovascular events due to higher levels of ESAs when used for target hemoglobin greater than 11 g/dl.[22][23][24] These events are likely related to the effect of ESAs on vascular remodeling and causing vasoconstriction.[25] CHOIR trial also showed that patients requiring higher levels of ESAs to achieve target hemoglobin had worse outcomes.[22] The discovery of stated side effects of ESAs, when used to target high normal hemoglobin levels, raised questions about the benefits of ESAs beside avoidance of transfusions, which has led to growing interest in looking for alternative etiologies and thus, management for anemia of CKD.

Patients with CKD have increased risk of iron deficiency, due to impaired dietary iron absorption, chronic bleeding due to platelet dysfunction from uremia, frequent phlebotomy, and blood trapping in the dialysis apparatus. This deficiency, in addition to depletion of the circulating iron pool by stimulation of erythropoiesis by ESAs, makes iron supplementation the core of treatment of anemia in CKD. Due to decreased absorption of oral iron, intravenous iron is preferable in hemodialysis patients.[26][27]

KIDGO recommends target transferrin saturation between 20 to 30% and ferritin level 100 to 500 ng/mL in patients with CKD who are not on dialysis. In patients with ESRD on dialysis receiving intravenous iron, goal transferrin saturation of 30 to 50% and ferritin higher than 200 ng/mL.[28] Iron has correlations with a risk of acute toxicity and infection, which should be weighed against the benefits in individual patients.

Unlike the general population, high serum ferritin levels are not predictive of hemoglobin responsiveness in renal failure patients. Finally, there is no level of erythropietin that can be considered adequate for defining renal anemia. Thus, erythropoietin levels should not regularly be measured in the evaluation of patients with renal anemia.

Differential Diagnosis

Aplastic anemia

Prognosis

There are many patients with renal failure who will not respond to erythropoiein and this is important as it is an important predictor of adverse cardiac events. Two factors that lead to unresponsiveness include iron deficiency and inflammation. High levels of CRP predict resistance to erythropoietin in dialysis patients. To enhance responsiveness to erythropoietin, iron supplements are recommended.

Complications

Anemia of renal disease is an independent risk factor for death. It has been shown to promote faster progression of left ventricular hypertrophy, peripheral oxygen demand and worsening of cardiac outcomes. More important anemia of renal failure leads to depression, fatigue, stroke, reduced exercise tolerance and increased rate of re-admissions.

Long term treatment with erythropoietin can cause hypertension, vasoconstriction, and seizures.

Deterrence and Patient Education

Eat a healthy diet

Take iron and multivitamin supplements

Pearls and Other Issues

Anemia of renal disease is common and is chiefly due to a decrease in erythropoietin production

It is necessary to investigate other treatable causes of anemia in renal failure patients

Erythropoietin levels are not indicative of anemia in renal failure patients. One should target a hemoglobin level of no more than 11.5 g/dl.

Enhancing Healthcare Team Outcomes

The management of the anemia of CKD is complex because it is not a simple matter of giving patients more blood transfusions or erythropoietin. Both these products have serious adverse effects when given chronically. One should never assume that anemia of renal disease is solely due to lack of erythropoietin, it may be due to poor nutrition or chronic illness- so a thorough workup is essential to determine the cause.

To manage patients on dialysis with anemia requires an integrated approach by an interprofessional team consisting of the nephrologist, PCP including the nurse practitioner, physician assistant, physician, nursing, pharmacy, and occasionally also a hematologist may be necessary to help achieve the best possible outcomes. The dialysis nurse should always monitor vital signs and obtain total blood counts to determine the level of anemia. The pharmacists should educate the patient about the importance of iron supplements because without iron, many patients develop resistance to erythropoietin.

Further, anemia of renal disease is also associated with adverse cardiac outcomes and hence the patient's cardiopulmonary status has to be monitored for life.

Finally, the involvement of a nutritionist is essential for avoidance and/or treatment of the deficiency of vitamins that can exacerbate the anemia of kidney disease.

Outcomes

The outcomes for patients with anemia of renal disease are guarded. Many develop adverse cardiac events that lead to a high mortality rate. Too much iron from blood transfusions also affects outcomes. Finally, chronic use of erythropoietin has been associated with severe hypertension, stroke and heart failure.

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A 65-year-old female presents to the clinic with a chief complaint of fatigue and dyspnea on exertion. Her past medical history is significant for chronic kidney disease stage II and diabetes mellitus type 2. Her physical examination is unremarkable except for a grade II systolic murmur heard best at the upper left sternal border and tachycardia. Her laboratory evaluation shows a hemoglobin of 8.5 g/dL and a mean corpuscular volume of 70 fL. Her ferritin level is 1000 ng/mL, and transferrin saturation is 10%. Her estimated glomerular filtration rate (eGFR) is 60 mL/minute. What is the next step in the management of this patient?

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A 55-year-old female with chronic kidney disease not on dialysis presents to the physician's office for the follow up of her anemia. On the last visit, a month ago, hemoglobin was 8.5 g/dl, but she was asymptomatic. Today, she is complaining of shortness of breath that she experienced on her morning run for the past two weeks so much that she had to stop multiple times to catch her breath. Blood work-up today shows hemoglobin 8 g/dl, serum iron 50 micrograms/dL, transferrin saturation 18%, and ferritin 100 ng/mL. Which of the following is the next step of management?

Reassure the patient that her blood work is typical of patients with chronic kidney disease (CKD) and her shortness of breath is likely related to a non-renal cause

Echocardiogram and chest x-ray

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A 65-year-old male with a past medical history of hypertension, diabetes mellitus type 2, chronic kidney disease stage III, presents to the clinic for a well visit. He has no complaints and reports exercising regularly. His laboratory evaluation reveals hemoglobin of 9.9 g/dL, mean corpuscular volume of 85 fL, with 35% transferrin saturation and a ferritin level of 600 ng/mL. His methylmalonic acid and homocysteine levels are normal. His last colonoscopy was 8 years ago at which time 3 hyperplastic polyps were removed. What is the likely cause of his anemia?

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A 65-year-old male with chronic kidney disease due to hypertension not on dialysis follows up for dyspnea on exertion that started two months ago. At that time, his hemoglobin level was 8 g/dl. Iron studies showed serum iron 80 ug/dl, transferrin saturation 32%, and ferritin 900 ng/mL. Other etiologies of dyspnea were ruled out with normal vitamin B12 and folate levels, normal TSH and echocardiogram showing an ejection fraction of 60-65% with no abnormalities. He has required transfusions with packed red blood cells twice since the presentation. He is offered the treatment option of erythropoiesis-stimulating agent, to which he agrees. However, he is worried about his new job that requires frequent travel. Which of the following is the best option for this patient?

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A 70-year-old male with presents with fatigue, lightheadedness, and shortness of breath on exertion for the past 3 months. He had the same complaint previously years back, which resolved after he started taking iron supplements. Physical examination reveals pallor and mild lower extremity pitting edema. He is a retired coal miner. His medical history is remarkable for hypertension and chronic kidney disease (CKD). Blood pressure is controlled with amlodipine 10 mg daily. Blood work during the current visit shows hemoglobin of 8.5 g/dl, serum iron of 65 micrograms/dL, transferrin saturation of 40%, and ferritin of 800 ng/mL. Peripheral smear showed normocytic normochromic cells interspersed with some microcytic cells. Which of the following is the next step in the management of this patient?

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A 55-year-old white female with a history of chronic kidney disease secondary to hypertension presents for annual follow up. Her blood pressure has been stable on amlodipine and lisinopril. The patient inquires about a low level of hemoglobin, of 12 g/dl, found on blood work done in an urgent care for pneumonia last month. Her hemoglobin has been stable, 12-13 g/dl in the past two years. Iron profile done three months ago ruled out iron deficiency. She states that her father used to get erythropoietin injections for the treatment of anemia of kidney disease. She is currently asymptomatic. What is the next step in management?

Tell the patient that her anemia does not warrant treatment, as her hemoglobin is greater than 11 g/dl and due to the reported side effects including thrombosis, adverse cerebrovascular and cardiovascular events when erythropoiesis-stimulating agents (ESAs) were used to target higher hemoglobin levels

Give intravenous iron infusion

Start treatment with erythropoietin

Repeat CBC in 2 weeks

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A 70-year-old woman is evaluated for fatigue and exertional dyspnea developing over several months. Medical history is significant for longstanding hypertension, but she has not been adherent with her medications. On physical examination, vital signs are normal except for blood pressure of 170/110 mm Hg. She is frail, with the pallor of mucous membranes and nail beds. The remainder of the examination is normal. Blood work shows hemoglobin 9 g/dl, MCV 85 fL, leukocyte count 7700/microL, platelet count 380,000/microL, creatinine 1.8 mg/dl, reticulocyte count 1%, ferritin 130 ng/ml, iron binding capacity 270 mcg/dL, iron 80 mcg/dL. Folate and vitamin B12 are within a normal range. The peripheral blood smear shows normal erythrocyte morphology without schistocytes. On kidney ultrasonography, kidneys are small bilaterally, suggesting chronic kidney disease. Which of the following is the most likely cause of this patient's anemia?

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A 63-year-old man is evaluated for increasing fatigue and exertional dyspnea over the past five months. Medical history is notable for diabetes mellitus, hypertension, and chronic kidney disease. Medications are insulin glargine, metformin, enalapril, aspirin, and atorvastatin. On physical examination, vital signs are normal. Pallor is noted. Examination findings are otherwise normal. Laboratory studies show a hemoglobin level of 9.5 g/dL (11 g/dL 1 year ago), reticulocyte count of 1% of erythrocytes, and serum creatinine level of 2.0 mg/dL (1.6 mg/dL 1 year ago). Serum haptoglobin, iron, ferritin, and folate levels; total iron-binding capacity; vitamin B12 level; and liver chemistry studies are normal. The stool guaiac test result is negative for occult blood. Which of the following is the most appropriate next step in management?

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Hsu CY,McCulloch CE,Curhan GC, Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the Third National Health and Nutrition Examination Survey. Journal of the American Society of Nephrology : JASN. 2002 Feb; [PubMed]

McClellan WM,Flanders WD,Langston RD,Jurkovitz C,Presley R, Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. Journal of the American Society of Nephrology : JASN. 2002 Jul; [PubMed]

Wang GL,Jiang BH,Rue EA,Semenza GL, Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proceedings of the National Academy of Sciences of the United States of America. 1995 Jun 6; [PubMed]

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